My copy of The Deeper Genome: Why there's more to the human genome than meets the eye has arrived and I've finished reading it. It's a huge disappointment. Parrington makes no attempt to describe what's in your genome in more than general hand-waving terms. His main theme is that the genome is really complicated and so are we. Gosh, golly, gee whiz! Re-write the textbooks!
You will look in vain for any hard numbers such as the total number of genes or the amount of the genome devoted to centromeres, regulatory sequences etc. etc. [see What's in your genome?]. Instead, you will find a wishy-washy defense of ENCODE results and tributes to the views of John Mattick.
John Parrington is an Associate Professor of Cellular & Molecular Pharmacology at the University of Oxford (Oxford, UK). He works on the physiology of calcium signalling in mammals. This should make him well-qualified to write a book about biochemistry, molecular biology, and genomes. Unfortunately, his writing leaves a great deal to be desired. He seems to be part of a younger generation of scientists who were poorly trained as graduate students (he got his Ph.D. in 1992). He exhibits the same kind of fuzzy thinking as many of the ENCODE leaders.
Let me give you just one example.
My copy of John Parrington's new book, The Deeper Genome: Why there is more to the human genome than meets the eye, is due to arrive in about three weeks. However, we already have a number of clues about what's in the book [see How the genome lost its junk according to John Parrington]. The excerpt on Amazon [How the genome lost its junk] tells us that Parrington is aware of the controversy surrounding the ENCODE project but comes down on the side of ENCODE.
That view is shared by science writer Claire Ainsworth who wrote a review in New Scientist: Its' so last century.1 Ainsworth is a freelance science writer with a Ph.D. in developmental genetics from Oxford (Oxford, UK). She is co-founder of SciConnect, a company that teaches science communication skills to scientists.
Here's what she says in her review ....
John Parrington is an associate professor in molecular and cellular pharmacology at the University of Oxford. In The Deeper Genome, he provides an elegant, accessible account of the profound and unexpected complexities of the human genome, and shows how many ideas developed in the 20th century are being overturned.
Take DNA. It's no simple linear code, but an intricately wound, 3D structure that coils and uncoils as its genes are read and spliced in myriad ways. Forget genes as discrete, protein-coding "beads on a string": only a tiny fraction of the genome codes for proteins, and anyway, no one knows exactly what a gene is any more.
A key driver of this new view is ENCODE, the Encyclopedia of DNA Elements, which is an ambitious international project to identify the functional parts of the human genome. In 2012, it revealed not only that the protein-coding elements of DNA can overlap, but that the 98 per cent of the genome that used to be labelled inactive "junk" is nothing of the sort. Some of it regulates gene activity, some churns out an array of different kinds of RNA molecules (RNAs for short), some tiny, some large, many of whose functions are hotly debated. Parrington quotes ENCODE scientist Ewan Birney as saying at the time, "It's a jungle in there. It's full of things doing stuff." And that is one of the most apt genome metaphors I've ever read.
People, including science writers, can have different opinions about the validity of the ENCODE results and whether most of our genome is junk. They can also have different opinions about whether many of the ideas developed in the 20th century are still valid. However, I think it's only fair to at least acknowledge that others may have different opinions.
Ainsworth must be aware of the controversy over ENCODE's claim that most of our genome has a function. She could have pointed out that Parrington supports the function side but many prominent scientists support the junk DNA side. She could have noted that there have been several scientific papers published since 2012 that defend the concept of junk DNA—and defend it very well.
A good science journalist can express an opinion on a scientific controversy but good science journalists are obliged to point out to their readers that this is just an opinion and there are many expert scientists who disagree.
The readers of this New Scientist book review will think that ENCODE was the last word on the debate and that's not good science reporting.
1. The title of the online version is "DNA is life's blueprint? No, there's far more to it than that."
My copy of Junk DNA by Nessa Carey has arrived and I'm working my way through it. It really is as bad as we imagined.
Here's an example (pp. 34-36). She describes a situation where an angry baboon might smash an expensive watch. If you hide the watch in large rolls of insulation, the baboon is less likely to cause damage.
And the insulation theory of junk DNA was built on the same premise. The genes that code for proteins are incredibly important. They have been subjected to high levels of evolutionary pressure, so that in any given organism, the individual protein sequence is as good as it's likely to get. A mutation in DNA—a change in a base pair—that changes the protein sequence is unlikely to make a protein more effective. It's more likely that a mutation will interfere with a protein's function or activity in a way that has negative consequences.
The problem is that our genome is constantly bombarded by potentially damaging stimuli in our environment. We sometimes think of this as a modern phenomenon, especially when we consider radiation from disasters such as those at the Chernobyl or Fukushima nuclear plants. But in reality this has been an issue throughout human existence. From ultraviolet radiation in sunlight to carcinogens in food, or emission of radon gas from granite rocks, we have always been assailed by potential threats to our genomic integrity. Sometimes these don't matter that much. If ultraviolet radiation causes a mutation in a skin cell, and the mutation results in the death of that cell, it's not a big deal. We have lots of skin cells; they die and are replaced all the time, and the loss of one extra is not a problem.
But if the mutation causes a cell to survive better than its neighbours, that's a step towards the development of a potential cancer, and the consequences of that can be a very big deal indeed. For example, over 75,000 new cases of melanoma are diagnosed every year in the United States, and there are nearly 10,000 deaths per year from the condition. Excessive exposure to ultraviolet radiation is a major risk factor. In evolutionary terms, mutations would be even worse if they occurred in eggs or sperm, as they may be passed on to offspring.
If we think of our genome as constantly under assault, the insulation theory of junk DNA has definite attractions. If only one in 50 or our bases is important for protein sequence because the other 49 base pairs are simply junk, then there's only a one in 50 chance that a damaging stimulus that hits a DNA molecule will actually strike an important region.
There are two obvious difficulties with the insulation theory of junk DNA. The first is that Nessa Carey believes that a lot of noncoding DNA is functional. If she's correct, that requires a great deal of insulating DNA if it's going to protect the functional parts. You can't have it both ways.
The second problem is that it doesn't pass the Onion Test. (I don't think the Onion Test is mentioned in the book but I haven't finished it yet.)
I'm sure you can come up with other objections.
Here's how I like to think of this explanation using the field of bullets analogy popularized by David Raup in his book Extinction: Bad Genes or Bad Luck.
Imagine an automatic machine gun in a pillbox firing 10 rounds a second. It swivels from left to right spraying bullets at random across a field. The enemy has only one grenade and in order to silence the machine gun, some soldier has to run across the field avoiding the bullets until he gets within throwing distance of the pillbox.
Will the soldier's chances be increased if he lines up side-by-side with 99 other soldiers (no grenades) and they all charge together? No.
What if all 100 soldiers line up in single file with the man holding the grenade at the back? That will work.
So, the only way that the insulation theory works is if the extra DNA forms a tight shield around the important functional DNA and physically protects it from cosmic rays or UV light. But this DNA is already "shielded" by a plasma membrane, a nuclear membrane, and various histones; not to mention all the other protein molecules, carbohydrates, and water molecules inside the cell. It's difficult to see what advantage DNA molecules have in direct shielding.
None of these problems are discussed in the book.
The journal Genomics is a journal devoted to the study of genomes. It describes itself like this ...
Genomics is a forum for describing the development of genome-scale technologies and their application to all areas of biological investigation.
As a journal that has evolved with the field that carries its name, Genomics focuses on the development and application of cutting-edge methods, addressing fundamental questions with potential interest to a wide audience. Our aim is to publish the highest quality research and to provide authors with rapid, fair and accurate review and publication of manuscripts falling within our scope.
They claim that all submissiosn are subjected to rigorous peer review and only 25-30% of submissions are accepted for publication.
The composition of genomes is important so it's no surprise that the journal is interested in publishing articles that address the junk DNA debate. In fact, it is so interested that it is going to devote a special issue to the subject for publication in February 2016.
That's the good news. Now for the bad news ....
Special issue on the functionality of genomic DNAs
Guest Editors:
Prof. Shi Huang
State Key Laboratory of Medical Genetics
Central South University , China
huangshi@sklmg.edu.cn
Prof James Shapiro
Department of Biochemistry and Molecular Biology
University of Chicago
jsha@uchicago.edu
The field of genome evolution and population genetics has for the past half of a century assumed that genomic DNA can be divided into functional and non-functional (“junk”) regions. Experimental molecular science has found little evidence for this assumption. A majority of the noncoding parts of the human genome are transcribed, and numerous experimental researchers have now recognized an important functional role in the so called junk DNA regions, such as syn sites, lncRNA, psudogene transcripts, antisense transcripts, microRNA, and mobile elements. In fact, evidence for functional constraints on noncoding genome regions has long been recognized. New theoretical frameworks based on less arbitrary foundations have also appeared in recent years that can coherently account for the reality of far more functional DNAs, as well as all other major known facts of evolution and population genetics. Nonetheless, there still remains a large gap in opinions between bench scientists in experimental biology and those on the theory side in bioinformatics and population genetics. This special issue will aim to close that gap and provide a view of evidence from a perspective that all genome regions have (or can easily acquire) functionality.
The special issue on the functionality of genome will focus on the following tentative topics:
- Theoretical foundation for all genome regions to be functional. It will cover both the theory and all major features of genome evolution.
- Functional studies on junk DNA regions, including lncRNA sequences, viral DNAs and mobile elements
- Functionalities associated with genome spatial organization in the nucleus
- Isocores and compositional constraints on genomes
- Genetic basis of complex traits and diseases focusing on the collective effects of normal genetic variations
- Cancer genomics
- Roles of repetitive DNA elements in major evolutionary transitions
- Correlations of genome composition and organismal complexity
- Epigenetics
- Evo Devo and extended synthesis
Important dates:
First submission date: July 1, 2015
Deadline for paper submissions: October 1, 2015
Deadline for final revised version: December 1, 2015
Expected publication: February 2016
Some of you will recognize the names of the guest editors. Jim Shapiro is one of the poster boys of Intelligent Design Creationism because he attacks evolutionary theory. He's one of the founders of the "The Third Way."
You may be less familiar with Shi Huang. He is also part of the Third Way movement but we've recently learned a lot more about him because he posts comments under the name "gnomon." You can see some of his comments in this thread: Ford Doolittle talks about transposons, junk DNA, ENCODE, and how science should work. Shi Huang appears to have a great deal of difficulty expressing himself in a rational manner.
Those guest editors will publish papers that "... provide a view of evidence from a perspective that all genome regions have (or can easily acquire) functionality." In other words, skeptics need not apply.
The controversy is over the amount of junk DNA in genomes. There are two sides in this controversy. Many scientists think there is abundant and convincing evidence that most of our genome is junk. Other scientists think that most of our genome is functional. It looks like Genomics is only interested in hearing from the second group of scientists. That's why they appointed guest editors with an obvious bias. Those guest editors also happen to be skating very close to the edge of kookdom.
This is not how a credible science journal is supposed to behave.
Read it at" Genetics: We are the 98%. Here's the important bit ...
Finally, Junk DNA, like the genome, is crammed with repetitious elements and superfluous text. Bite-sized chapters parade gee-whizz moments of genomics. Carey's The Epigenetics Revolution (Columbia University Press, 2012) offered lucid science writing and vivid imagery. Here the metaphors have been deregulated: they metastasize through an otherwise knowledgeable survey of non-coding DNA. At one point, the reader must run a gauntlet of baseball bats, iron discs, Velcro and “pretty fabric flowers” to understand “what happens when women make eggs”. The genome seems to provoke overheated prose, unbridled speculation and Panglossian optimism. Junk DNA produces a lot of DNA junk.
The idea that the many functions of non-coding DNA make the concept of junk DNA obsolete oversells a body of research that is exciting enough. ENCODE's claim of 80% functionality strikes many in the genome community as better marketing than science.
Nessa Carey is a science writer with a Ph.D. in virology and she is a former Senior Lecturer in Molecular Biology at Imperial College, London.
She has written a book on junk DNA but it's not available yet (in Canada). Judging by her background, she should be able to sort through the controversy and make a valuable contribution to informing the public but, as we've already noted Nessa Carey and New Scientist don't understand the junk DNA debate.
Casey Luskin has a copy of the book so he wrote a blog post on Evolution News & Views. He's thrilled to find someone else who dismisses junk DNA and "confirms" the predictions of Intelligent Design Creationism. I hope Nessa Carey is happy that the IDiots are pleased with her book [New Book on "Junk DNA" Surveys the Functions of Non-Coding DNA].
There's some controversy over the rate of mutations in humans. The latest summary comes from science journalist Ewen Callaway, a Senior Reporter for Nature, writing on March 10, 2015: DNA mutation clock proves tough to set.
Theme
Mutation
-definition
-mutation types
-mutation rates
-phylogeny
-controversies
Let's review what we know. The first thing we have to do is define "mutation" [What Is a Mutation?]. A mutation is any alteration of the nucleotide sequence of a genome. It includes substitutions, insertions, and deletions.
The mutation rate can be described and defined in many ways. For most purposes, we can assume that it's equivalent to the error rate of DNA replication since that accounts for the vast majority of substitutions. Substitutions are far more numerous than most insertions and deletions. (But see, Arlin Stoltzfus on The range of rates for different genetic types of mutations).
A recent issue of Nature contains a report on plant micro-RNAs (Lauressergues et al., 2015). The authors found that certain genes for plant micro-RNAs encoded short peptides in the micro-RNA precursors and those peptides seemed to have a biological function. What this means is that part of the longer precursor RNA that is cleaved to produce the final micro-RNA may have a function that wasn't recognized. If you thought that the part of the precursor that was thought to be discarded as useless junk was, in fact, junk, then you were wrong—at least for some genes.
This is not a big deal and the authors of the paper don't even mention junk DNA.
The paper was reviewed by Peter M. Waterhouse and Roger P. Hellens in the same issue (Waterhouse and Hellens, 2015). They think it's a big deal. Here's what they say,
I really hate it when publishers start to hype a book several months before we can read it, especially when the topic is controversial. In this case, it's Oxford University Press and the book is "The Deeper Genome" Why there is more to the human genome than meets the eye." The author is John Parrington.
The title of the promotion blurb is: How the Genome Lost its Junk on the Canadian version of the Oxford University Press website. It looks like this book is going to be an attack on junk DNA.
We won't know for sure until June or July when the book is published. Until then, the author and the publisher will have free reign to sell their ideas without serious opposition or push back.
Here's the prepublication hype. I'm going to buy this book and read it as soon as it becomes available. Stay tuned for a review.
Francis Collins is the Director of the National Institutes of Health (NIH) in the USA. He spoke recently at the 33rd Annual J.P. Morgan Healthcare Conference in San Francisco (Jan. 12-15, 2015). His talk was late in the afternoon on Tuesday, January 13, 2015. You can listen to the podcast on the conference website [J.P. Morgan Healthcare Conference].
The important bit is at the 30 minute mark where he comments on a question about junk DNA. This is what Francis Collins said last week ...
I would say, in terms of junk DNA, we don't use that term any more 'cause I think it was pretty much a case of hubris to imagine that we could dispense with any part of the genome as if we knew enough to say it wasn't functional. There will be parts of the genome that are just, you know, random collections of repeats, like Alu's, but most of the genome that we used to think was there for spacer turns out to be doing stuff and most of that stuff is about regulation and that's where the epigenome gets involved, and is teaching us a lot.
What seems like "hubris" to Francis Collins looks a lot like scientific evidence to me. We know enough to say, with a high degree of confidence, that most (~90%) of our genome is junk. And we know a great deal about the data that Collins is probably referring to (ENCODE)—enough to conclude that it is NOT saying what he thinks it says.
It would be bad enough if this were just another confused scientist who doesn't understand the data [see Five Things You Should Know if You Want to Participate in the Junk DNA Debate] but he's not just any scientist. He's a powerful man who talks to politicians all the time and deals with the leaders of large corporations (e.g. the J.P. Morgan Conference). If Francis Collins doesn't understand the fundamentals of genome science then he could mislead a lot of people.
Collins has many colleagues surrounding him at NIH and other agencies in Washington. These scientists also make important decisions about American science. I'm assuming that he reflects their opinion as well. If not, then why aren't they educating Francis Collins?
Hat Tip: Ryan Gregory
One of the most important problems in biochemistry & molecular biology is the role (if any) of pervasive transcription. We've known for decades that most of the genome is transcribed at some time or other. In the case of organisms with large genomes, this means that tens of thousand of RNA molecules are produced from regions of the genome that are not (yet?) recognized as functional genes.
Do these RNAs have a function?
Most knowledgeable biochemists are aware of the fact that transcription factors and RNA polymerase can bind at many sites in the genome that have nothing to do with transcription of a normal gene. This simply has to be the case based on our knowledge of DNA binding proteins [see The "duon" delusion and why transcription factors MUST bind non-functionally to exon sequences and How RNA Polymerase Binds to DNA].
If you have a genome containing large amounts of junk DNA then it follows, as night follows day, that there will be a great deal of spurious transcription. The RNAs produced by these accidental events will not have a biological function.
MicroRNAs are a special class of small functional RNA molecules. The functional RNA is only about 22 nucleotides long and most of the well-characterized examples bind to mRNA to inhibit translation and/or destabilize the message.
The big questions for many of us are how many different microRNAs are there in a typical cell and how many of them have a real biological function. These questions are, of course, part of the debate over junk DNA. Are there thousands and thousands of microRNA genes in a typical genome and does this mean that there's a lot less junk DNA than some of us claim?
The journal Cell Death and Differentiation has devoted a special issue to microRNAs [Special Issue on microRNAs – the smallest RNA regulators of gene expression]. There are four reviews on the subject but none of them address the big questions.
That didn't stop the journal from leading off with this introduction ...
It is now well recognised that the majority of non-protein-coding genomic DNA is not “junk” but specifies a range of regulatory RNA molecules which finely tune protein expression. This issue of CDD contains an editorial and 5 reviews on a particular class of these regulatory RNAs, the microRNAs (miRs) of around 22 nucleotides, and which exert their effects by binding to consensus sites in the 3'UTRs of mRNAs. The reviews cover the role of miRs from their early association with CLL to other forms of cancer, their importance in the development of the epidermis and their potential as disease biomarkers as secreted in exosomes.
I'm not certain what the editors mean when they say that "it is now well recognised ..." I interpret this to mean that there are a large number of scientists who are completely uniformed about the structure of genomes and the debate over junk DNA. In other words, it is now well recognized that some scientists don't know what they are talking about.
I don't know any expert who would claim that 50% of large genomes consist of genes that specify regulatory RNAs involved in fine-tuning protein expression. Do you?
On a related issue, Wilczynska and Bushell begin their review with ...
Since their discovery 20 years ago, miRNAs have attracted much attention from all areas of biology. These short (~22 nt) non-coding RNA molecules are highly conserved in evolution and are present in nearly all eukaryotes.
Sequence conservation is an important criterion in deciding whether something is functional. In order to use conservation as a measure of function you have to establish some standards that let you distinguish between sequences that are "conserved" by negative selection and those that have drifted apart by random genetic drift.
What do Wilczynska and Bushell mean when they say that microRNAs are "highly conserved"? The most highly conserved genes exhibit about 50% sequence identify between prokaryotes and eukaryotes. They are almost identical within mammals. Other highly conserved genes are about 80% identical within animals (e.g. between insects and mammals). As far as I know, the sequences of most putative microRNAs aren't even similar within mammals and certainly not between mammals and fish.
The phrase "highly conserved" has become meaningless. It's now a synonym for "conserved" because nobody ever wants to just say "conserved" and they certainly don't want to say "moderately conserved" or "weakly conserved" even if it's the truth.
How biochemistry students can become multi-millionaires by making plants more efficient. Has someone finally succeeded?
Living organisms need carbon to grow and divide. Many get their carbon atoms from organic molecules such as glucose or acetate that have been synthesized in other species.
Most organisms can fix carbon directly from carbon dioxide by a variety of different reactions but this isn't necessarily the primary source of carbon atoms. (We can fix carbon using pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and phosphoenolpyruvate carboxykinase (PEPCK) among others.)
This is another story about press releases. In this case, it's an article published by ScienceDaily: Non-coding half of human genome unlocked with novel sequencing technique. It's almost a direct copy of a press release put out by Texas A&M University (Texas, USA): Texas A&M Biologists Unlock Non-Coding Half of Human Genome with Novel DNA Sequencing Technique.
Let's begin by looking at the actual paper (Aldrich and Maggert, 2014). Here's the abstract.
Heterochromatin is a significant component of the human genome and the genomes of most model organisms. Although heterochromatin is thought to be largely non-coding, it is clear that it plays an important role in chromosome structure and gene regulation. Despite a growing awareness of its functional significance, the repetitive sequences underlying some heterochromatin remain relatively uncharacterized. We have developed a real-time quantitative PCR-based method for quantifying simple repetitive satellite sequences and have used this technique to characterize the heterochromatic Y chromosome of Drosophila melanogaster. In this report, we validate the approach, identify previously unknown satellite sequence copy number polymorphisms in Y chromosomes from different geographic sources, and show that a defect in heterochromatin formation can induce similar copy number polymorphisms in a laboratory strain. These findings provide a simple method to investigate the dynamic nature of repetitive sequences and characterize conditions which might give rise to long-lasting alterations in DNA sequence.
Biology News Net has become a joke. It's rare to see a paper that it hasn't mangled or a press release that it hasn't fallen for, hook line and sinker. I read it for amusement.
A recent report began with ... [Parts of genome without a known function may play a key role in the birth of new proteins]
Researchers in Biomedical Informatics at IMIM (Hospital del Mar Medical Research Institute) and at the Universitat Politècnica de Catalunya (UPC) have recently published a study in eLife showing that RNA called non-coding (lncRNA) plays an important role in the evolution of new proteins, some of which could have important cell functions yet to be discovered.
That sounds intriguing. Maybe I should read the paper even though it's in eLife.
It took a little more work than I expected, but eventually I found the paper (Ruiz-Orera et al., 2014). Here's the abstract.
Deep transcriptome sequencing has revealed the existence of many transcripts that lack long or conserved open reading frames (ORFs) and which have been termed long non-coding RNAs (lncRNAs). The vast majority of lncRNAs are lineage-specific and do not yet have a known function. In this study, we test the hypothesis that they may act as a repository for the synthesis of new peptides. We find that a large fraction of the lncRNAs expressed in cells from six different species is associated with ribosomes. The patterns of ribosome protection are consistent with the translation of short peptides. lncRNAs show similar coding potential and sequence constraints than evolutionary young protein coding sequences, indicating that they play an important role in de novo protein evolution.
The study suggests that a lot of "noncoding" RNAs are being translated. The products appear to be short polypeptides of less than 100 residues.
New protein encoding genes do arise from time to time although the number of proven examples is very small. Let's assume, for the sake of argument, that a new gene arises about once every million years in a given lineage. That would mean about five new genes in humans since they split from chimpanzees and that seems about right for an upper limit.
Now, if you make a lot of junk RNAs by randomly transcribing junk DNA, then some of them will undoubtedly make short polypeptides. There's a chance that random mutations will create a peptide that takes on a functional role of some kind. There's an even smaller chance that this function will confer a selective advantage on the individual carrying the mutation. That's one way new genes are born.
Is this a reason for carrying a huge amount of junk DNA in your genome and making thousands of lncRNAs? Is the potential to make a new gene one million years in the future sufficient explanation for the preservation of junk DNA? The answer is "no."
You don't have junk DNA because it might proven useful in the future. You have it because you can't get rid of it. You don't transcribe your junk DNA because it might be useful, you transcribe it because the general properties of RNA polymerase and transcription factors don't allow for perfect discrimination between real genes and junk DNA. Junk transcripts aren't translated because they contain potential coding regions, they are sometimes translated because they must, by chance, contain some open reading frames.
Sloppiness might, by accident, lead to new genes but that's not why things are sloppy. If having junk DNA were a clear advantage for future evolution then the genomes of all extant lineages should have lots of junk DNA and should make lots of lncRNAs.
Ruiz-Orera, J., Messeguer, X., Subirana, J.A., and Alba, M.M. (2014) Long non-coding RNAs as a source of new peptides. eLife 2014;3:e03523 [doi: 10.7554/eLife.03523]
Many genes encode proteins and many other genes specify functional RNAs that do not encode proteins. The "RNA genes" include the classic genes for ribosomal RNAs and tRNAs as well as genes for very well-studied RNAs that carry out catalytic roles in the cell. There are a myriad of small RNAs required for things like splicing and regulation. All species, both prokaryotes and eukaryotes, contain genes for a wide variety or functional RNAs.
Eukaryotes seem to have an abundance of genes for small RNAs that perform a number of specific roles in regulation etc. They also have a lot of DNA regions complementary to long noncoding RNAs or lncRNAs (also lincRNA). The definition of long noncoding RNAs seems arbitrary and ambiguous [see Long Noncoding RNA]. Some of them might even encode proteins!
As a general rule, these RNAs are longer than 200 bp and some scientists put the cutoff at 1000 bp. Simple eukaryotes, such as yeast, don't have a lot of lncRNAs but eukaryotes with large complex genomes that are full of junk DNA seem to have a lot of different lncRNAs. The DNA regions1 that specify these lncRNAs ar not conserved. This strongly suggest that many of the lncRNAs are spurious nonfunctional transcripts even though some of them have well-characteized functions [see On the function of lincRNAs].
As usual, we have a definition problem. Are "lncRNAs" just a generic class of long noncoding RNAs that include thousands of nonfunctional molecules that are nothing more than junk RNA? Or, does the term "lncRNA" refer only to the subset that has a function? If it's the latter, then we should probably be referring to "putative" lncRNAs most of the time since the vast majority have not been shown to have a function. (There are about 10,000 of these RNAs in humans.)
I don't see how you can avoid the elephant in the room whenever you talk about lncRNAs. The most important question in NOT whether some of them have a function—that was demonstrated 30 years ago. The important question is whether the majority, or even a substantial minority, have a function.
That's why I was eager to read a short review by Rinn and Guttman in a recent issue of Science (Rinn and Guttman, 2014). They describe two lncRNAs that probably play a role in organizing chromatin within the nucleus (Xist and Neat1, both fram mammals). That's cool.
Then they say,
Collectively, these studies suggest that lncRNAs may shape nuclear organization by using the spatial proximity of their transcription locus as a means to target preexisting local neighborhoods. lncRNAs can in turn modify and reshape the organization of these local neighborhoods to establish new nuclear domains by interacting with various protein complexes, including chromatin regulators. Once established, a lncRNA can act to maintain these nuclear domains through active transcription and recruitment of interacting proteins to these domains. While the mechanism for how lncRNAs establish these domains is not fully understood, it is becoming increasingly clear that lncRNAs are important at all levels of nuclear organization—exploiting, driving, and maintaining nuclear compartmentalization.
It sure sounds like they are describing a particular function (nuclear organization) to the majority of lncRNAs. But what if 90% of all 10,000 lncRNAs have no function and what if only 100 of the remaining functional lncRNAs are involved in nuclear organization? That means there are 900 functional lncRNAs that play a different role in the cell?
If that were true, you would write that last paragraph very differently. If you recognize the elephant, you might say something like this ....
Very few lncRNAs have been shown to have a function and there's a very good chance that most of them are spurious transcripts that have no function. However, a small percentage do seem to have a function. In this review we have identified some long noncoding RNAs that appear to be involved in nuclear organization. We propose to call these RNAs "noRNAs" for "nuclear organizer RNAs" on the grounds that once a function has been identified we should stop referring to them as lncRNAs.
But that doesn't sound nearly as exciting as the subtitle of the article, "Long noncoding RNAs may function as organizing factors that shape the cell nucleus" or the quotation that's prominently displayed in a box in the center of the page, "... it is becoming increasingly clear that IncRNAs are important in all levels of nuclear organization—exploiting, driving, and maintaining nuclear compartmentalization." When did science become so dedicated to hype over substance? I must have missed the memo.
1. I use "DNA regions" instead of "genes" because the definition of a gene requires that the gene product be functional. You can't call them genes unless you have demonstrated that the RNA has a function.
Rinn, J. and Guttman, M. (2014) RNA and dynamic nuclear organization. Science 345"1240-1241 [doi: 10.1126/science.1252966]
Most people don't understand the consequences of genetic testing. You may think that you can handle all of the data and information but think again.
This is the story of someone who got their DNA tested by a commercial company and he persuaded his parents to participate as well. What could possibly go wrong? The title of the article tells the story: With genetic testing, I gave my parents the gift of divorce.
Turns out he has a half-brother! His father never mentioned that he had a son with another woman.
At first, I was thinking this is the coolest genetics story, my own personal genetics story. I wasn't particularly upset about it initially, until the rest of the family found out. Their reaction was different. Years of repressed memories and emotions uncorked and resulted in tumultuous times that have torn my nuclear family apart. My parents divorced. No one is talking to my dad. We're not anywhere close to being healed yet and I don't know how long it will take to put the pieces back together.
It's not always true that having information is better than not having information. If you beleive that then you are very naive.
Apparently I flunked the Behe challenge [Laurence Moran's Sandwalk Evolves Chloroquine Resistance]. Let's review what happened.
In his book, The Edge of Evolution, Michael Behe calculated the odds of a malaria parasite developing resistance to chlorquine by assuming that two separate mutations were necessary. Here's what he said on page 57 ...
How much more difficult is it for malaria to develop resistance to chloroquine than to some other drugs? We can get a good handle on the answer by reversing the logic and counting up the number of malarial cells needed to find one that is immune to the drug. For instance, in the case of atovaquone, a clinical study showed that about one in a trillion cells had spontaneous resistance. In another experiment, it was shown that a single amino acid change at position number 268 in a single protein, was enough to make P. falciparum resistant to the drug. Se we can deduce that the odds of getting that single mutation are roughly one in a trillion.
Michael Behe thinks the main thesis of his book, The Edge of Evolution, has been vindicated by a recent paper (Summers et al., 2014). He is wrong, as I discussed in a previous post [Michael Behe and the edge of evolution].
PZ Myers and Ken Miller have already made the same points that I make but the IDiots never listen when their view are challenged. Instead, they go on the attack and claim that the latest publications refute evolution and support Intelligent Design Creationism.
Behe is certain that he's right. He's so certain that he has issued a challenge to Myers and Miller [An Open Letter to Kenneth Miller and PZ Myers]. I'm going to try and do some calculations to meet his challenge but I'm not certain if I'm doing them correctly. Please help me find any mistakes.
This is Part III of several "Function Wars"1 posts.
How much of the human genome is conserved?
The first post in this series covered the various definitions of "function" [Quibbling about the meaning of the word "function"]. In the second post I tried to create a working definition of "function" and I discussed whether active transposons count as functional regions of the genome or junk [The Function Wars: Part II]. I claim that junk DNA is DNA that is nonfunctional and it can be deleted from the genome of an organism without affecting its survival, or the survival of its descendants.
The best way to define "function" is to rely on evolution. DNA that is under selection is functional. But how can you determine whether a given stretch of DNA is being preserved by natural selection? The easiest way is to look at sequence conservation. If the sequence has not changed at the rate expected of neutral changes fixed by random genetic drift then it is under negative selection. Unfortunately, sequence conservation only applies to regions of the genome where the sequence is important. It doesn't apply to DNA that is selected for its bulk properties.
